Aging can be defined as progressive deterioration of various biological functions with gradual increase in the risk of disease and death. This phenomenon is very complex with both genetic and non-genetic factors in action. The heritability of human longevity is estimated to be somewhere between 0.15 and 0.35. The action of genetic contributors can be modified by environment, resulting in altered risk of aging. One fundamental task in understanding its etiology is dissecting the relative contributions of genetic and non-genetic factors. My long-term research interest lies in the hereditary aspect of human aging and how the manifestation of the genetic basis is influenced by non-genetic factors during the life history of individuals. Based on twin study designs, I plan to identify genetic and epigenetie risk factors involved in human aging. In principle, the genetic aspect of healthy aging in twins can be studied by investigating concordant dizygotic twins, and the eipgenetic aspect by investigating discordant monozygotic twins with appropropate controls. The genetic study is to test the hypothesis that long-lived family members share common genetic variants that contribute to longevity and healthy aging. The epigenettc study is to test the hypothesis that the environmental contribution to the phenotypic variation of healthy aging is mediated by epigenetie mechanisms. To achieve these goals, I propose four Specific Aims. Aim 1 is to recruit twins who are at least 68 years old by means of the Mid-Attantic Twin Registry (MATR), which is currently the largest twin registry in the U. S. According to data recently provided by the MATR, there are over 700 twin pairs available for this study. Aim 2 is to compile their healthy aging profiles and estimate their biological ages. For this purpose, we will survey participating twins for various health variables, which include medical history, physical and cognitive functioning. Aim 3 is to identify genes associated with healthy aging and longevity. For this aim, we will first identify genomic regions linked to healthy aging. Next, we will fine map the regions by applying case-control association analysis. Aim 4 is to establish DNA methylation as an epigenetie mechanim of healthy aging, and for this aim, we will study DNA methylation status of twins.